Diabetes is considered as the world's fastest growing chronic disease. Patients with type 1 or type 2 diabetes have to inject insulin 3-4 times a day to maintain physiological glucose levels and it involves monitoring of blood glucose levels and administration of insulin injections every day for the rest of the diabetic patient's life.
Insulin therapy has evolved in the last century from using purified bovine or porcine insulin to biosynthetic human insulin to recombinant human insulin, and more recently to the use of recombinant insulin analogues, which represent the 3rd generation of human insulin (Hirsch 2005). Despite the great advances seen in the development of various types of insulin, the administration of insulin is still generally through subcutaneous route. Subcutaneous administration has lead to several treatment-associated sequelae. Insulin therapy or intensification of insulin therapy commonly results in weight gain in both Type 1 and Type 2 Diabetes (Kalra et al. 2010). This weight gain can be excessive and can adversely affect the patient's cardiovascular risk profile. This is possibly due to the ‘unphysiological’ pharmacokinetic and metabolic profile following subcutaneous administration. Thus, injected insulin can avoid first-pass metabolism, and therefore large quantities of insulin are available to stimulate adipocytes and increase glucose and lipid uptake into cells. High local concentrations of insulin may result in lipodystrophy, possibly due to areas of local down-regulation of insulin receptors in adjacent adipocytes (Regis et al. 2007). Further, due to the variation in the fat content under different sites of injection and variable release from the site of injection, it is often impossible to achieve strict glycemic control which leads to high variability in blood glucose levels between and within individuals.
Additionally, many patients are needle-phobic, and there is a high rate of non-compliance in diabetic patients, which leads to improper treatment and the development of undesirable sequelae that could have been prevented with correct treatment.
Recently, the potential for oral delivery of insulin has been explored by several workers (Madhav 2011). However, the use of oral delivery mechanisms for insulin is prevented by two main barriers. Firstly, the harsh acidic and proteolytic environment in the stomach and the intestine leading to rapid degradation of proteins such as insulin when administered orally; and secondly, there is a requirement to have a transport mechanism for insulin to be taken up and across the intestinal epithelial cells, with subsequent release into the circulation in pharmaceutically optimal concentrations (Madhav 2011).
The presence of insulin receptors in the upper part of the intestine has been reported (Buts et al, 1990, 1994, 1997a, 1997b; Fernández-Moreno et al, 1986, 1987, 1988; Forgue-Lafitte, 1980; Georgiev et al, 2003; Stilmant et al, 2001) and has the potential to be exploited for the gastrointestinal uptake of insulin. However, for it to be biologically active, Insulin has to be in its monomeric form. The purified insulin protein exists as a monomer at low pH, but self-associates to form a hexamer at basic pH. At pH in the range of 4.5 to 6.5, the insulin aggregates to form a precipitate. In order to utilize the naturally occurring receptors, there is a need for technology that can protect insulin from proteolytic degradation and maintain the conditions for insulin to be presented to its receptors in a monomeric form.
In the view of aforementioned limitations, there is a need to achieve efficient delivery of insulin through oral administration in its monomer form to avoid proteolysis in the gastrointestinal tract.